Regorafenib improves progression-free survival and disease-control rate in patients with advanced GIST after failure to prior therapy with at least imatinib and sunitinib
Randomised, phase III, GRID trial of regorafenib in patients with metastatic and/or unresectable GIST
- Date : 18 Jun 2012
- Topic : Gastrointestinal cancers
Oral multikinase inhibitor regorafenib demonstrated substantial activity in a previous phase II trial in patients with gastrointestinal stromal tumour (GIST) after failure of both imatinib and sunitinib. The GRID phase III, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of regorafenib in this population with unmet clinical need. The results show improvement in progression-free survival and disease-control rate with regorafenib, and were presented by Dr George Demetri of the Dana-Farber Cancer Institute, Boston, during the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO), 1-5 June, Chicago, USA.
Eligible patients had metastatic and/or unresectable GIST, objective failure to prior therapy with imatinib and sunitinib (progressive disease on, or intolerance to imatinib, and progressive disease on sunitinib), ≥1 measurable lesion, ECOG performance status 0 or 1. Patients were randomised 2:1 to receive best supportive care plus either regorafenib 160 mg po once daily (3 weeks on/1 week off) or placebo. The primary endpoint was progression-free survival measured according modified RECIST 1.1 criteria by independent central review. Secondary endpoints included overall survival, disease-control rate (defined as rate of partial response plus stable disease lasting for ≥12 weeks), response rate and duration, safety and correlative genotype analyses. At time of progressive disease, patients were eligible for unblinding and crossover to open-label regorafenib.
Improvement in treatment outcomes in patient population with unmet clinical needs
In 2011, 234 patients were screened; 199 were randomised (133 in regorafenib arm and 66 to placebo). Patients were stratified at randomisation according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms.
The primary endpoint was met: median progression-free survival was 4.8 months for regorafenib vs. 0.9 months for placebo. Hazard ratio for progression-free survival was 0.27, p<0.0001. Progression-free survival rates at 3 and 6 months were 60% and 38% for regorafenib vs. 11% and 0% for placebo. Disease-control rate was 53% with regorafenib vs. 9% with placebo. The HR for overall survival was 0.77 with 85% patients in placebo arm having crossed over to regorafenib.
The most common treatment-emergent adverse events (> grade 3) in the regorafenib arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhoea (8%).
The authors concluded that this randomised trial demonstrated that regorafenib significantly improved progression-free survival and disease-control rate in patients with advanced GIST after failure of at least prior imatinib and sunitinib. Regorafenib was well tolerated, with adverse effects as expected for this class and manageable with dose modifications.
The pharmaceutical company Bayer plans to file application for marketing approval for regorafenib in the treatment of GIST in the second half of this year. Onyx Pharmaceuticals is the marketing partner for regorafenib in the USA. Last month the company filed for approval in the USA and EU for regorafenib as a treatment of metastatic colorectal cancer. The drug is also testing in a number of other tumour types, including renal cancer.
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